Lowe Syndrome, or oculocerebrorenal syndrome (OCRL), is a genetic disease caused by mutations in the OCRL gene, which encodes a phosphatidylinositol 5-phosphatase. Mutations in this gene lead to accumulation of phosphoinositides. Individuals with Lowe Syndrome have neurological problems, including mental retardation and behavioral problems. A promising strategy for the treatment of this disease will be to develop drugs that inhibit proteins that cause the accumulation of these phosphoinositides. To identify potential drug targets we propose to perform genetic screens for mutations that ameliorate the disease phenotypes in an animal model of this disease. We are studying mutations in synaptojanin (unc-26), a phosphatidylinositol 5-phosphatase related to OCRL, in the nematode Caenorhabditis elegans. These mutants are uncoordinated and have defects in membrane metabolism in the nervous system. We propose to perform genetic screens for suppressor mutations in this strain. Preliminary data indicate that second site mutations can partially alleviate the uncoordinated and slow growing phenotypes of these mutants. The mutated genes will be identified to determine the proteins encoded by these genes. Some of these proteins are likely to be involved in the regulation of synthesis of phosphoinositides. In the future, drugs that specifically inhibit these proteins can be developed as therapeutic agents to treat the symptoms of Lowe Syndrome patients. We have three specific aims: Specific Aim 1. Identify genetic suppressors of synaptojanin mutants (unc-26). Specific Aim 2. Test candidate genes for unc-26. Specific Aim 3. Clone the genes identified in the suppressor screen. The specific aims outlined in this grant application represent a necessary first step for the treatment of Lowe Syndrome. Because individuals with Lowe Syndrome lack the OCRL protein, it is not a candidate for drug therapy and further characterization of this protein is not likely to lead to future treatment. Instead, we must identify proteins that promote synthesis of the phosphoinositides. If inhibition of such proteins in cells cultured from Lowe Syndrome patients cause a decrease in PIP2 levels, this would provide the basis for future development of small molecules that inhibit protein function. In the future, cooperation between C. elegans geneticists, cell biologists, and structural biochemists may become a standard approach for rational drug design for many genetic diseases. [unreadable] [unreadable]